RESUMEN
This research is based on intention to prepare and test 3beta-hydroxy and 3beta,28-dihydroxy analogues of new pro-apoptotic derivatives (betulinines) using selective hydrolysis procedure and strategic protective groups. The evaluation of cytotoxicity of prepared compounds on several tumor cell lines using an MTT test was our interest. It was found that hydrolysis of acetates in betulinines afforded compounds with higher cytotoxicity in case of 18-lupene-21-ones (e.g., ethyl 3beta-hydroxy-21-oxolup-18-en-28-oate), whereas hydrolysis of the 18-lupene-21,22-diones gave less active derivatives.
Asunto(s)
Antineoplásicos/síntesis química , Triterpenos/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Hidroxilación , Concentración 50 Inhibidora , Relación Estructura-Actividad , Triterpenos/farmacologíaRESUMEN
In this study, the relationships between the chemical structure and cytotoxic activity of betulinic acid (1) derivatives were investigated. Eight lupane derivatives (1-8), one of them new (6), five diosphenols (9-13), four of them new (10-13), two new norderivatives (14 and 15), five seco derivatives (16-20), four of them new (16, 17, 19, and 20), and three new seco-anhydrides (21-23) were synthesized from 1, and their activities were compared with the activities of known compounds. The effects of substitution on the A-ring and esterification of the carboxyl group in position 28 on cytotoxicity were of special interest. Significant cytotoxic activity against the T-lymphoblastic leukemia cell line CEM was found in diosphenols 9 and 13 (TCS(50) 4 and 5 micromol/L) and seco-anhydrides 22 and 23 (TCS(50) 7 and 6 micromol/L). All compounds were also tested on cancer cell lines HT 29, K562, K562 Tax, and PC-3, and these confirmed activity of diosphenols 9, 10, and 11 and anhydride 22. Diosphenols, as the most promising group of derivatives, were further tested on four more lines (A 549, DU 145, MCF 7, SK-Mel2).
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/farmacología , Técnicas Químicas Combinatorias , Triterpenos/síntesis química , Triterpenos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Triterpenos Pentacíclicos , Relación Estructura-Actividad , Células Tumorales Cultivadas , Ácido BetulínicoRESUMEN
Cellular screening of various synthetic triterpenoid compounds formally derived from lupane has identified a number of analogues as potential anticancer drug candidates. Here we describe the synthesis and structure-activity relationships of betulin and betulinic acid derivatives containing an E-ring modified with different oxygen functions. Thus compounds containing the lup-18-en-21-one, lup-18-ene-21,22-dione, 18,19-secolupane, and the highly oxygenated 18,19-secolupane systems, as well as des-E-lupane derivatives, were prepared from the readily available natural pentacyclic triterpene betulin using oxidative procedures. These compounds were named betulinines. We demonstrate that only selected compounds, particularly those containing a lupane E-ring-derived unsaturated ketone or diketone function, possessed in vitro cytotoxic activity against tumor cell lines, suggesting a structure-activity relationship.